The Experts below are selected from a list of 189 Experts worldwide ranked by ideXlab platform
Kyriacos C. Nicolaou - One of the best experts on this subject based on the ideXlab platform.
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DNA Binding and Cleavage Modes of Shishijimicin A.
Journal of the American Chemical Society, 2019Co-Authors: Hao Zhang, Emmanuel N. Pitsinos, Kyriacos C. NicolaouAbstract:Although shishijimicin A and its extreme potencies against an array of cancer cell lines have been known for more than a decade, its assumed DNA-cleaving mechanism has not been substantiated as yet. Herein we report studies that reveal binding and scission of double-stranded DNA by shishijimicin A. The results of these studies support the proposed hypothesis that DNA strand scissions are caused by 1,4-benzenoid diradicals formed by Bergman Cycloaromatization of the enediyne core of shishijimicin A upon activation by thiols. In addition, double-stranded supercoiled DNA-cleavage experiments with shishijimicin A in competition with known minor groove binders, UV spectroscopic studies, and electrophoretic analysis were utilized to clarify the binding mode of the molecule to DNA. These investigations indicate that shishijimicin A binds to the minor groove of double-stranded DNA and that its β-carboline moiety plays a role in the binding through intercalation. In addition, due to the fact that naked linker regions of DNA in the interphase and metaphase of eukaryotic cells are unprotected by histone proteins during entire cell cycles and because these unprotected regions of DNA are vulnerable to attack by DNA binders, it was concluded that the observed double-strand DNA cleavage and very low sequence selectivity by shishijimicin A may account for its extraordinary cytotoxicity.
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Redox-controlled Bergman Cycloaromatizations. Designed enediynes with DNA-cleaving properties and antitumor activity
Journal of the American Chemical Society, 1992Co-Authors: Kyriacos C. Nicolaou, A. Liu, Z.‐j. Zeng, S. MccombAbstract:Enediynes 7 and 9 were designed for their potential to act as radical-generating species upon oxidation to the corresponding quinone. Their synthesis entailed a chromium-nickel-mediated ring closure of iodo aldehyde 6. Investigations with these molecules and their derivatives 8 and 10 demonstrated the anticipated acceleration of the Bergman Cycloaromatization of the oxidized species as compared to the reduced compounds and potent DNA-cleaving and antitumor properties
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Design, synthesis, and study of simple monocyclic conjugated enediynes. The 10-membered ring enediyne moiety of the enediyne anticancer antibiotics
Journal of the American Chemical Society, 1992Co-Authors: Kyriacos C. Nicolaou, G. Zuccarello, C. Riemer, V. A. Estevez, Wei-min DaiAbstract:Following the discovery of the enediyne anticancer antibiotics, investigations were initiated directed toward the design, synthesis, and study of simple monocyclic conjugated enediynes. In this article the synthesis of the parent 10-membered ring enediyne found in the enediyne natural products and its properties are described. In addition to the parent hydrocarbon 27, the synthetic methodology developed based on the Ramberg-Blcklund reaction delivers a series of higher ring homologs (17-22) and the water soluble version of the 10-membered ring compound 47. Molecular mechanics calculations on these systems led to a number of geometrical parameters which correlated well with their tendencies to undergo the Bergman Cycloaromatization reaction. Kinetic studies on the Bergman Cycloaromatization of the 10-membered ring enediynes 27 and 47 led to the following thermodynamic values: 27, energy of activation (E,) = 23.8 kcal/mol, AG* (37 "C) = 24.6 kcal/mol; 47, energy of activation (E,) = 31.5 kcal/mol, AG' (37 "C) = 24.8 kcal/mol. The designed enediyne 47 showed potent DNA-cleaving properties becoming the first synthetic molecule to mimic the action of the naturally occurring enediynes in this regard.
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Molecular design and chemical synthesis of potent enediynes. 2: Dynemicin model systems equipped with C-3 triggering devices and evidence for quinone methide formation in the mechanism of action of dynemicin A
Journal of the American Chemical Society, 1992Co-Authors: Kyriacos C. Nicolaou, Wei-min DaiAbstract:Continuing the theme of the preceding article, this paper describes the synthesis and chemical properties of designed enediynes related to dynemicin A. These model systems are equipped with triggering devices at C-3 of the aromatic nucleus. The design of these compounds (1 and 2) was based on the hypothesis that a C-3 phenolic group generated in situ would be capable of promoting epoxide opening and subsequent Bergman Cycloaromatization according to the dynemicin A cascade
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Molecular design and chemical synthesis of potent enediynes. 1: Dynemicin model systems equipped with N-tethered triggering devices
Journal of the American Chemical Society, 1992Co-Authors: Kyriacos C. Nicolaou, Wei-min Dai, Peter E. Maligres, T. Suzuki, Sebastian Wendeborn, Raj K. ChadhaAbstract:In this article the molecular design and chemical synthesis of a series of enediynes (12-19, Chart I) related to the dynemicin A structure and carrying N-tethered triggering devices are described. The design envisioned the [(arylsulfonyl)ethoxy]carbonyl group attached at the nitrogen atom as a triggering device for the Bergman Cycloaromatization reaction because of its ability to undergo β-elimination under basic conditions, liberating the labile free amine intermediate.A number of tethering groups on the aromatic ring were also installed in these systems for future incorporation of other desirable moieties such as delivery systems and solubility enhancers.The chemical synthesis of the desired systems proceeded from the corresponding quinoline intermediates through acetylide additions to quinoline(intermolecular) and carbonyl( intramolecular) functionalities as the key steps.Bergman cycloaromatisation experiments under basic and acidic conditions demonstrated the abilities of these compounds to generate benzenoid diradicals.A number of potent DNA-cleaving compounds and cytotoxuc agents emerged from these studies
Wei-min Dai - One of the best experts on this subject based on the ideXlab platform.
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Design, synthesis, and study of simple monocyclic conjugated enediynes. The 10-membered ring enediyne moiety of the enediyne anticancer antibiotics
Journal of the American Chemical Society, 1992Co-Authors: Kyriacos C. Nicolaou, G. Zuccarello, C. Riemer, V. A. Estevez, Wei-min DaiAbstract:Following the discovery of the enediyne anticancer antibiotics, investigations were initiated directed toward the design, synthesis, and study of simple monocyclic conjugated enediynes. In this article the synthesis of the parent 10-membered ring enediyne found in the enediyne natural products and its properties are described. In addition to the parent hydrocarbon 27, the synthetic methodology developed based on the Ramberg-Blcklund reaction delivers a series of higher ring homologs (17-22) and the water soluble version of the 10-membered ring compound 47. Molecular mechanics calculations on these systems led to a number of geometrical parameters which correlated well with their tendencies to undergo the Bergman Cycloaromatization reaction. Kinetic studies on the Bergman Cycloaromatization of the 10-membered ring enediynes 27 and 47 led to the following thermodynamic values: 27, energy of activation (E,) = 23.8 kcal/mol, AG* (37 "C) = 24.6 kcal/mol; 47, energy of activation (E,) = 31.5 kcal/mol, AG' (37 "C) = 24.8 kcal/mol. The designed enediyne 47 showed potent DNA-cleaving properties becoming the first synthetic molecule to mimic the action of the naturally occurring enediynes in this regard.
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Molecular design and chemical synthesis of potent enediynes. 2: Dynemicin model systems equipped with C-3 triggering devices and evidence for quinone methide formation in the mechanism of action of dynemicin A
Journal of the American Chemical Society, 1992Co-Authors: Kyriacos C. Nicolaou, Wei-min DaiAbstract:Continuing the theme of the preceding article, this paper describes the synthesis and chemical properties of designed enediynes related to dynemicin A. These model systems are equipped with triggering devices at C-3 of the aromatic nucleus. The design of these compounds (1 and 2) was based on the hypothesis that a C-3 phenolic group generated in situ would be capable of promoting epoxide opening and subsequent Bergman Cycloaromatization according to the dynemicin A cascade
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Molecular design and chemical synthesis of potent enediynes. 1: Dynemicin model systems equipped with N-tethered triggering devices
Journal of the American Chemical Society, 1992Co-Authors: Kyriacos C. Nicolaou, Wei-min Dai, Peter E. Maligres, T. Suzuki, Sebastian Wendeborn, Raj K. ChadhaAbstract:In this article the molecular design and chemical synthesis of a series of enediynes (12-19, Chart I) related to the dynemicin A structure and carrying N-tethered triggering devices are described. The design envisioned the [(arylsulfonyl)ethoxy]carbonyl group attached at the nitrogen atom as a triggering device for the Bergman Cycloaromatization reaction because of its ability to undergo β-elimination under basic conditions, liberating the labile free amine intermediate.A number of tethering groups on the aromatic ring were also installed in these systems for future incorporation of other desirable moieties such as delivery systems and solubility enhancers.The chemical synthesis of the desired systems proceeded from the corresponding quinoline intermediates through acetylide additions to quinoline(intermolecular) and carbonyl( intramolecular) functionalities as the key steps.Bergman cycloaromatisation experiments under basic and acidic conditions demonstrated the abilities of these compounds to generate benzenoid diradicals.A number of potent DNA-cleaving compounds and cytotoxuc agents emerged from these studies
Graham B. Jones - One of the best experts on this subject based on the ideXlab platform.
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Oxa-enediynes: probing the electronic and stereoelectronic contributions to the Bergman Cycloaromatization.
The Journal of organic chemistry, 2002Co-Authors: Graham B. Jones, Justin M. Wright, George Hynd, Justin K. Wyatt, Robert S. Huber, Michael W. Kilgore, Robert P. Sticca, Philip M Warner, Richard S. PollenzAbstract:Efficient routes to three classes of 10-membered oxa-enediynes are presented. The electronic and stereoelectronic contributions to half-lives are supported by density functional theory calculations. One member of this class cyclizes to give an isochroman which binds to and degrades the aryl hydrocarbon receptor (AhR).
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Oxa-enediynes: probing the electronic and stereoelectronic contributions to the Bergman Cycloaromatization.
The Journal of organic chemistry, 2002Co-Authors: Graham B. Jones, Justin M. Wright, George Hynd, Justin K. Wyatt, Philip Warner, Robert S. Huber, Michael W. Kilgore, Robert P. Sticca, Richard S. PollenzAbstract:A series of halogen-substituted cyclic enediynes were prepared with use of carbenoid coupling strategy. DFT analysis, initially used to identify synthesis candidates, was also employed to rationalize the propensity for Cycloaromatization of the compounds. In all cases studied the halogen atom had a strongly retardative effect on the thermal Bergman Cycloaromatization reaction. The isolation of the first C-9 monochloroenediyne is noteworthy, and may find application in prodrug design.
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Halo-enediynes: probing the electronic and stereoelectronic contributions to the Bergman Cycloaromatization.
The Journal of organic chemistry, 2002Co-Authors: Graham B. Jones, Justin M. Wright, George Hynd, Justin K. Wyatt, Philip Warner, Robert S. Huber, Michael W. Kilgore, Robert P. Sticca, Richard S. PollenzAbstract:A series of halogen-substituted cyclic enediynes were prepared with use of carbenoid coupling strategy. DFT analysis, initially used to identify synthesis candidates, was also employed to rationalize the propensity for Cycloaromatization of the compounds. In all cases studied the halogen atom had a strongly retardative effect on the thermal Bergman Cycloaromatization reaction. The isolation of the first C-9 monochloroenediyne is noteworthy, and may find application in prodrug design.
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Protein-degrading enediynes: library screening of Bergman Cycloaromatization products.
Organic letters, 2000Co-Authors: Graham B. Jones, Justin M. Wright, George Hynd, Justin K. Wyatt, Molly Yancisin, Myles BrownAbstract:A screening method based on Bergman Cycloaromatization products was applied to a compact library of estrogenic-enediyne hybrids. An enediyne candidate identified from the screen was subsequently synthesized, and it induced temperature- and concentration-dependent degradation of human estrogen receptor α upon Cycloaromatization.
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Electronic control of the Bergman Cycloaromatization: synthesis and chemistry of chloroenediynes.
Organic letters, 2000Co-Authors: Graham B. Jones, Gary W. PlourdeAbstract:A series of cyclic mono- and dichloroenediynes have been prepared using an intramolecular carbenoid coupling reaction. The halogen atom had a retardative effect on Bergman Cycloaromatization in every case examined, and atom transfer chemistry was demonstrated, resulting in formation of adducts.
Joseph M. O'connor - One of the best experts on this subject based on the ideXlab platform.
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Photoactivated Transition-Metal Triggers for Ambient Temperature Enediyne and Dienyne Cyclization: Ruthenium-η6-Naphthalene Complexes
Organometallics, 2017Co-Authors: Pengjin Qin, Stephen K. Cope, Han Steger, Kate M. Veccharelli, Ryan L. Holland, David M. Hitt, Curtis E. Moore, Kim K. Baldridge, Joseph M. O'connorAbstract:A persistent challenge confronting potential applications of the Bergman Cycloaromatization reaction is the development of methods for spatiotemporal control of diradical formation. Photochemical variants (photo-Bergman Cycloaromatizations) have thus far met with limited success, failing completely in the case of acyclic enediynes. Here we describe the development of efficient photoactivated transition-metal complexes that allow for spatiotemporal control of enediyne Cycloaromatization at ambient temperatures. This strategy relies on air- and moisture-stable ruthenium naphthalene complexes that undergo photochemical dissociation of the naphthalene ligand, thereby generating coordination sites for enediyne binding and Cycloaromatization. The same ruthenium naphthalene complexes also trigger dienyne cyclization under photochemical conditions.
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Transition-Metal Hydrides as Hydrogen Atom Donors: Stronger Metal−Hydrogen Bonds Can Be Advantageous
Organometallics, 2008Co-Authors: Joseph M. O'connor, Seth J. FrieseAbstract:The tungsten hydride complex (η5-C5H5)W(CO)3H (1-W) functions as a hydrogen atom donor in the [(η5-C5Me5)Ru(NCMe)3]PF6-mediated Bergman Cycloaromatization reaction of (Z)-dodeca-4,8-diyn-6-ene. The strong M−H bond in 1-W does not react with the enediyne substrate but does react with the diradical arising from cyclization, thereby demonstrating the advantages of strong metal−hydrogen bonds in the hydrogen atom transfer reactions of metal hydrides with substrates involving alkenes and alkynes.
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Ruthenium-Mediated Cycloaromatization of Acyclic Enediynes and Dienynes at Ambient Temperature
Journal of the American Chemical Society, 2002Co-Authors: Joseph M. O'connor, Seth J. Friese, Mark S. TichenorAbstract:The ruthenium(II) cation, [Cp*Ru(NCMe)3]OTf (4), triggers the Bergman Cycloaromatization of acyclic endiynes at room temperature in THF solvent. Treatment of 1,2-di(1-alkynynyl)cyclopentenes (13-Me...
Richard S. Pollenz - One of the best experts on this subject based on the ideXlab platform.
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Oxa-enediynes: probing the electronic and stereoelectronic contributions to the Bergman Cycloaromatization.
The Journal of organic chemistry, 2002Co-Authors: Graham B. Jones, Justin M. Wright, George Hynd, Justin K. Wyatt, Robert S. Huber, Michael W. Kilgore, Robert P. Sticca, Philip M Warner, Richard S. PollenzAbstract:Efficient routes to three classes of 10-membered oxa-enediynes are presented. The electronic and stereoelectronic contributions to half-lives are supported by density functional theory calculations. One member of this class cyclizes to give an isochroman which binds to and degrades the aryl hydrocarbon receptor (AhR).
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Oxa-enediynes: probing the electronic and stereoelectronic contributions to the Bergman Cycloaromatization.
The Journal of organic chemistry, 2002Co-Authors: Graham B. Jones, Justin M. Wright, George Hynd, Justin K. Wyatt, Philip Warner, Robert S. Huber, Michael W. Kilgore, Robert P. Sticca, Richard S. PollenzAbstract:A series of halogen-substituted cyclic enediynes were prepared with use of carbenoid coupling strategy. DFT analysis, initially used to identify synthesis candidates, was also employed to rationalize the propensity for Cycloaromatization of the compounds. In all cases studied the halogen atom had a strongly retardative effect on the thermal Bergman Cycloaromatization reaction. The isolation of the first C-9 monochloroenediyne is noteworthy, and may find application in prodrug design.
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Halo-enediynes: probing the electronic and stereoelectronic contributions to the Bergman Cycloaromatization.
The Journal of organic chemistry, 2002Co-Authors: Graham B. Jones, Justin M. Wright, George Hynd, Justin K. Wyatt, Philip Warner, Robert S. Huber, Michael W. Kilgore, Robert P. Sticca, Richard S. PollenzAbstract:A series of halogen-substituted cyclic enediynes were prepared with use of carbenoid coupling strategy. DFT analysis, initially used to identify synthesis candidates, was also employed to rationalize the propensity for Cycloaromatization of the compounds. In all cases studied the halogen atom had a strongly retardative effect on the thermal Bergman Cycloaromatization reaction. The isolation of the first C-9 monochloroenediyne is noteworthy, and may find application in prodrug design.